Imidazol thiophan derivatives and process for the manufacture of same



Patented Mar. 11, 1947 IMIDAZOL THIOPHAN DERIVATIVES AND PROCESS FOR THEMANUFACTURE OF SAME Otto Schnider, Jean-Pierre Bourquin, and AndreGriissner, Basel,

Switzerland,

assignors to Hoffmann-La Roche Inc., Nutley, N. J., a corporation of NewJersey No Drawing. Application March .29, 1945, Serial No. 585,570. InSwitzerland April 26, 1944 19 Claims. 1

Biotin, which is of vital importance for many an organism, Wasrecognised to be a derivative of 3,4- (2-oxo-tetrahydroimidazol)-thiophan.

It has now been found that thiop-han-one-(3) carboxylic acid esters canbe used as starting materials for the manufacture of derivativescarrying in position 2 an alkyl radical or an omegasubstituted alkylradical. Compoundscarrying, apart from alkyl radicals, for instance thefollowing radicals, may be employed:omegahydroxya1ky1-,omega-alkoxyalkyl, omega-aryloxyalkylor omega-haloge-nalkyl-radicals.

The thiophan-one-(3)-carboxylic acid esters (I), which carry a suitablesubstituent in position 2, are initially converted into thecorresponding cyanohydrins (II) by means of hydrocyanic acid. The sameare saponified Without further purification and the resultingdicarboxylic acids (III) esterified. The3-hydroxythiophan-3,4-dicarboxylic acid esters (IV), substituted inposition 2, are oils capable of being distilled. Upon reacting withhalides of phosphorus and sulphur, e, g., thionyl chloride, they aretransformed into the 3-chlorine esters (V). By means of reducing agentsthe halogen can be eliminated, whereby the thiophan-3,4-dicarboxylicacid esters (VI), substituted in position 2, are obtained. From thesethe way leads to the corresponding acid azides, either by preparing thehydrazides (VII) by means of hydrazin hydrate and treating them withsodium nitrite, or by converting the free acids (VIII) obtained bysaponification into the acid chlorides (IX) and treating the latter Withsodium azide. By heating With alcohols, the 3,4-di-(carbethoxy-amino)-thiophans (XI), substituted in position 2, are obtained from theazides. On warming with hydrogen halides, e. g., hydrobromic acid, theyare converted into the salts of the corresponding 3,4-diamino-thiophans(XII) substituted in position 2. By stirring with phosgene in a Weaklyalkaline solution, the d,1- 3,4(2'-OX0 tetrahydroimidazol)-2-X-thiophans (XIII) are obtained therefrom.

CH-C-C 0 OR H IV OHrCH-CO O R In these formulae R stands for loweralkyl, and X is an alkyl radical or an omega-substituted alkyl radical.

This synthesis of compounds with the bicyclic I system XIII ischaracterised in that the amino ployable substancesshowing the activityof biotin.

Example 1 80 parts by weight of finely powdered potassium cyanide areadded to a solution of 188 parts by weight of2-methyl-3-oxo-thiophan-4.-carboxylic-acid-ethyl-ester in 500 parts byVolume of ether. While stirring and cooling well, 90 parts by volume ofconcentrated hydrochloric acid are added dropwise in the course of about2 hours. After evaporation of the 'ether, 300 parts by volume of ethylalcohol and 300 parts by volume of concentrated hydrochloric acid areadded to the remaining 2-methyl-3-hydroXy-3-cyano-thiophan-l-carboirylic acid-ethyl-ester; saponification iseffected by first slowly distilling 01f the alcohol and then allowingthe product to stand in a boiling water bath for another 2 hours. Byconcentration in vacuo, 2-methyl-3-hydroxythiophan-3,4-dicarboXy1ic acidis obtained, which can be converted into theZ-methyl-B-hydroxythiophan-3,4-dicarboxylic acid diethyl ester withoutfurther purification by means of ethyl alcohol and hydrochloric acid. Itboils at a pressure of 0.05 mm. at 101 to 102 C. as an almostcolourless, viscous oil.

262 parts by weight ofZ-methyl-S-hydroxythiophan-3,4-dicarboxylic-acid-diethyl-ester aredissolved in 500 parts by volume of chloroform and successively treatedwith 80 parts by volume of pyridine and 119 parts by volume of thionylchloride while cooling well with ice. The product is first allowed tostand for 2 hours and then heated for about 40 minutes in a boilingwater bath until the evolution of gas has ceased. Thereupon, the productis poured on ice, divided in a separating funnel and washed with waterand dilute sodium carbonate solution until neutral reaction sets in. TheZ-rnethyl-S-chloro-thiophan-3,4-dicarboxylic-acid-diethyl-esterseparated from the chloroform boils at a pressure of 0.1 mm. at 100 to102 C.

186 parts by Weight of sodium-iodide hydrate are added to a solution of280 parts by weight of2-methyl-3-chloro-thiophan-3,4-dicarboxylicacid-diethyl-ester in 4000parts by volume of 80 percent. acetic acid, and 1400 parts by weight ofzinc dust introduced in small portions in the.

course of about 4 hour while stirring. Each time slight warming sets in.After further 'stir- 250 parts by volume of absolute alcohol and thesolution heated under reflux with parts by weight of hydrazin hydratefor about 10 hours. After some time, the hydrazide begins toprecipitate. The precipitate augments in the course of heating. Aftercooling, the 2-methyl-thiophan- 3,4-dicarboXylic-acid-dihydrazide isseparated, dissolved and allowed to crystallise from hot water.sintering.

A solution of 218 parts by weight of Z-methylthiophan 3,4dicarboxylic-acid-dihydrazide in 670 parts by volume of 3 n-hydrochloricacid is covered with a layer of 2000 parts by volume of ether and asolution of 140 parts by weight of sodium nitrite in 800 part by volumeof water added drop by drop. The resulting acid azide is solubleinether. The other solution is separated from the salt solution when thereaction has come to an. end, the ether driven off and the2-methyl-thiophan-3,4-dicarboxylic-acid-diazide remaining behind as alight-yellowish. oil is treated with 2000 parts by volume of absolutealcohol. The clear solution is heated to about C., at which temperaturea vigorous evolution of nitrogen sets in, which lasts for abouthalfan-hour. The clear, almost colourless solution is treated with wateruntil it starts to get turbid and cooled. On filtering the colourlessZ-methyl- 3,4-di- (carbethoxyamino) -thiophan crystallising in fineneedles of melting point 182 to 183 C.

is obtained.

The same diurethan can be obtained by saponifying the2-methyl-thiophan-3,4-dicarboxylicacid-diethyl-ester, converting theresulting acid into the acid chloride (boiling point 12 mm./135- 137 C.)and reacting the same with sodium azide. The resulting oily,ether-soluble diazide turns into the 2-methyl-3,4.-(dicarbethoxyamino)-thiophan of melting point 182 to 183 C. on warming in absolute alcohol.

276 parts by weight of this urethane are heated for about 1 hour to 105to 110 C. together with 2760 parts by volume of 45 per cent. hydrobromicacid until the evolution of carbonic acid has come to an end. Onconcentration in vacuo, the 2-methyl-3,4-diamino-thiophan-dihydrobromide remains behind as a solid mass. It canbe dissolved and allowed to crystallise from a solution in diluteacetone or dilute alcohol. The colourless crystals, inclusive of 2crystal-water, melt at 225 to 227 C. with decomposition. The diamine ischaracterised by the following derivatives:

The 2-methyl-3,4-diureido-thiophan melts at 262 C. with decomposition.'The 2-methyl-3A- diamino-thiophan-dipicrate melts at 243 C. withdecomposition. The 2 -methyl- 3,4 -di-(benzoylring for about 12 hours,the zinc acetate is sepamino) -thiophan melts at 271-272 C'. The2-methyl-3,4-di-(acetylamino)rthiophan melts at parts by volume ofn-sodium-hydroxide, on the one hand, and parts by weight ofphosgene inform of a 20 per cent. solution in toluene, on

ately begin to precipitate.

is complete. 7 tion'and washed with water. The.3,4-(2'-oxotetrahydroimidazol) '-2 methyl-thiophan can 'be It melts at241 to 242 C. after previous 5. crystallised from a solution indiluteacetic acid or dilute alcohol. It is easily soluble in alcohols andacetic acid, less easily in acetone and diificult' ly in ether. benzeneand water. It carbonises nprolonged heating to 350-350 C.

Example 2 80 parts by weight of finely pulverised potassium cyanide areadded to a solution of 260 parts by weight of Z-(omega-methoxybutyl)-3-oxothiophan-d-carboxylic-acid-ethyl-ester in 540 parts by volume ofdibutyl ether and then 106 parts by volume of concentrated hydrochloricacid allowed to drop in during 8 hours while stirring and cooling withice. The reaction mixture is left to stand overnight at 0 C. Thecrystallised cyanohydrin with the potassium chloride is separated fromthe dibutyl-ether solution by suction. The separation of the cyanohydrinfrom the potassium chloride is eifected by dissolving the former inchloroform. Thechloroform solution is dried with sodium sulphate andafter filtration brought to dryness in vacuo at a bath temperature of 30C. The 2-(omega-methoxybutyl) -3-hydroxy-3-cyano-thiophan-4-carboxylic-acid-ethyl-ester, obtained in almost theoretical yield, has a meltingpoint of 88 C. The methyl ester'melts at 81.5 to 835 C.

287 parts by weight of 2 (omega-methoxybutyl) 3hydroxy-3-cyano-thiophan-4-carboxylic-acidethyl-ester are reacted with amixture of 600 parts by volume of concentrated hydrochloric acid, 300parts by volume of water and 1100 parts by volume of ethyl alcohol andboiled under reflux for 48 hours. After evaporation in vacuo, thesaponified product is converted into the 2- (omega-methoxybutyl)-3-hydroxy-thiophan-3,4- dicarboxylic-acid-diethyl-ester by means ofethyl alcohol and hydrogen-chloride gas. It boils at a pressure of 0.07mm. at 145147 C. as a lightyellow, viscous oil. The dimethy] ester boilsat a pressure of 0.09 mm. at 146-149" C.

334 parts by weight of 2-(0mega-methoxybutyl)-3-hydroxy-thiophan-3,4dicarboxylic acid diethyl-ester are dissolved in660 parts by volume of chloroform and reacted with 154 parts by weightof absolute pyridine and 231 parts by weight of thionyl chloride whilecooling with ice. Reaction and working-up in accordance with Example 1yield a yellowish-brown, viscous oil, viz.

2- (omega-methoxybutyl) -3-chloro-thiophan-3,4-dicarboxylic-acid-diethy1-ester, melting point 138-143 C. at 0.03 mm.The dimethyl ester boils at 134't0 137 C. under a pressure of 0.03 mm.

353 parts by weight of 2-(omega-methoxybutyl)-3-chloro-thiophan-3,a-dicarboxylic-acid-di ethyl-ester are dissolved in5100 parts by Volume of 80 per cent. acetic acid, 230 parts by weight ofpotassium iodide are added, and, while stirring, 1550 parts by weight ofzinc dust are introduced in small portions in the course of 4 hours at atemperature not exceeding 25 C. After working-up in accordance withExample 1, the 2 (omegamethoxybutyl-thiophan-3,4-dicarbo-xylic-acid-diethyl-ester boils as alight-yellowish oil at 148 to 150 C. under a, pressure of 0.03 mm.

The 2-(omega-methoxybutyl) -thiophan-3,4-di- 6carboxylic-acid-dihydrazide precipitates in colourless needles and has amelting point of 204 to 205 C. The same hydrazide is also obtained fromthe 2- (omega-methoxybutyl) -thiophan-3',4-dicarboxylic-acid-dimethyl-ester.

290 parts by weight of Z-(omega-methoxybutyl)-thiophan-3,4-dicarboxylic-acid dihydrazide are dissolved in 835 partsby volume of 3 n-hydrochloric acid, covered with. a layer of 8000 partsby volume of ether and reacted, while stirring and cooling with ice,with a solution of 138 parts by weight of sodium nitrite in 1000 partsby volume of water added drop by drop. The azide is isolated asdescribed in Example 1 and transformed into the urethane by means of7000 parts by volume of absolute alcohol. The fine, colourless needlesof Z-(omega-methoxybutyl) 3 l-diurethano-thiophan show a melting pointhydroxide, and while coo-ling with ice and while stirring, reacted with99 parts by weight of phosgene (in the form of a 20 per cent. solutionin toluene) and 2000 parts by volume of 'n-sodium hydroxide, the latterand the toluene-phosgene solution being added simultaneously and thereaction being effected at a pH of 7 to 8; The reaction product, afteraddition of glacial acetic acid, is brought to dryness in vacuo andrubbed,

with water. The 3,4-(imidazolidon-2)-2-(omega-bromobutyD-thiophan has amelting point of 1'75.5 C. after dissolving and allowing to crystallisefrom methanol.

Example 3 Apart from the crystallised dihydrazide of melting point 204to 205 C. obtained as a result of the preparation ofZ-(omega-methoxybutyl) -'thialuminum oxide. One of the isomericurethanes,

having a melting point of to 126 C., is obtained in crystalline form byeluting with benzene.

348 parts by Weight of Z-(omega-methoxybutyl) -3, l-diurethano-thiophanof melting point 125 to 126 C. are heated with 48 per cent. hydrobromicacid as described in Example 2. The resulting hygroscopic2-(omega-bromobuty1)-3,4- diamino-thiophan-dihydrobromide is convertedinto the 3,4-(imidazolidon-2) -2-(omega-bromobutyl) -thiophan by meansof phosgene. crystallised compound, from methanol, has a melting pointof 163 to 164 (3.; the mixture with the isomer of meltingp'oirit Theafter recrystallisation" aha-e26:

7' 175.5 C. shows considerable depression of the melting point. I

On chromatographically treating the oily urethanes, further isomers areobtained which can be worked up in the same manner. 1

We claim: 7 1. Process for the manufacture of a d,l-substance of thegeneral formula OH2CH-NH \CHCHN{I wherein the radical X is selected fromthe group consisting of alkyl, omega-methoxy alkyl and omega-halogenoalkyl, comprising converting 3- 'oXo-thiophan-4-carboxylic-acid-esters,which are substituted in position 2 by the radical X, into thecyano-hydrines, preparing therefrom by saponification and esterificationthe corresponding 3-hydroxy-3,4-dicarboxylic-acid-esters, eliminatingfrom these compounds the hydroxy-grcup by replacing it by halogen andsubsequently reducing the latter, reacting the thus obtained thiophan-3,4-dicarboxylic-acid-esters, carrying the radical X in position 2, withhydrazin hydrate, reacting upon the acid hydrazides with sodium nitritein order to obtain the acid azides and decomposing the latter byreacting with alcohol to yield the 3,4-diurethans, converting these byboiling with acids into the salts of the 3,4-diamino-thiophanssubstituted in position 2 by the radica1 X, and obtaining from thesediamines the 2-X-3,4-(2'-oxotetrahydroimidazol)-thiophans by means ofphosgene.

2. Process for the manufacture of d,l-2-methyl- 3,4-(2'-oXo-tetrahydroimidazo1) -thiophan, comprising converting2-methyl-3-oxo-thiophan-4- carboxylic-acid-esters into thecyanohydrines, preparing therefrom by saponiiication and esterificationthe corresponding 3-hydroxy-3,4.-dicarboxylic-acid-esters, eliminatingfrom these compounds the hydroXy-group by replacing it by halogen andsubsequently reducing the latter, reacting the thus obtained2-methy1-thio-phan-3,4-diii carboxylic-aoid-esters with hydrazinhydrate, reacting upon the acid hydrazides with sodium nitrite in orderto obtain the acid azides and decomposing the latter by reacting withalcohol to yield the 3,4-diurethans, converting these by boiling withacids into the salts of the 2-methyl-3,4- diamino-thiophans andobtaining from these diamines the2-methyl-3,4-(2-oXo-tetrahydroimidazol) -thiophans by means of phosgene.

3. Process for the manufacture of d,l-2- (omegamethoxy-butyl) -3,4- (2'oxo tetrahydroimidazo1) -thiophan, comprising converting 2-(omegamethoxy-butyl) -3-oxo-thiophan l carboxylicacid-esters into thecyano-hydrines, preparing therefrom by saponification and esterificationthe corresponding 3-hydroxy-BA-dicarboxylic-acidesters, eliminating fromthese compounds the hydroxy-group by replacing it by halogen andsubsequently reducing the latter, reacting the thus obtained2-(omega-methoxy-butyl)-thiophan-8,4- dicarboXylic-acid-esters withhydrazin hydrate,

reacting upon the acid hydrazides with sodium nitrite in order to obtainthe acid azides and decomposing the latter by reacting with alcohol tothiophan, comprising converting 2-(omega-bromo-butyl) -3-oXo-thiophan-4carboxylic acidesters into the cyano-hydrines, preparing therefrom bysaponiiication and esterification the corresponding 3-hydroxy-3,i-dicarboxylic-acid-es ters, eliminating from these compounds thehydroxy-group by replacing it by halogen and sub-' ber selected from thegroup consisting of alkyl radicals and aliphatic omega-substituted-alkylradicals.

6. As compositions of matter, d,l2-substituted-' 3,4-(2- 0X0tetrahydroimidazrol) thiophans, in which the substituent in the2-position is alkyl.

'1. As compositions of matter, d,l-2-substituted- 3,4-(2'- oxotetrahydroimidazol) thiophans, in which the substituent in thezepo'sitio'n is aliphatic omcga-substituted-alkyl. V

8. As compositions of matter, d,l-2-substituted- 3,4-(2'- oxotetrahydroimidazol) thiophans, in which the substituent in the2-position is methyl.

9. As compositions of matter, d,l2-substituted- 3,4-(2- oxotetrahydroimidazol) thiophans, in which the substituent in the 2-position is omegaalkoXy-alkyl.

18. As compositions of matter, d,l-2-substituted-3,4(2-oXo-tetrahydroirnidazol) -thiophans, in which the substituent in the2-position is omegaalkoxy-butyl. a

11. As compositions of matter, d,1-2-substituted-3,4-(2'-oXo-tetrahydroimidazol) -thiophans, in

which the substituent in the methoxy-butyl. 7

12. As compositions of matter, d,1-2-substituted-SA-(2'-oX0-tetrahydroimidazol) -thiophans, in

2 -position is omegawhich the substituent in the 2 positionis'omega-ed-3,4-(2- c-Xo tetrahydroimida zol) thiophans,

which comprises converting 2-substituted-3,4-di- (caro-alkoxyamino)-thiophans, in which the substituent in the 2-positi0nis a memberselected from the group consisting of alkyl radicals and aliphaticomega-substituted-alkyl radicals, to d,l- Z-substituted '-3, i-(2-- 0x0tetrahydroimidazol) thiophans, in which the substituent in the2-position is a member selected from the group consisting of alkylradicals and alpihatic omega-substituted-aikyl radicals. a

16. A process in accordance with claim 15 which comprises converting thedi-carbalkoxyaminothicphan to a di-hydrohalide salt of 2substituted-3,4-diamino thiophan by means ofa hydroaliphaticomega-substituted-alkyl radicals, is con- 15 10 verted to adi-hydrobromide-amino salt by means of hydrobromic acid, followed byconversion of said salt to the imidazol-thiophan.

OTTO SCHNIDER. JEAN-PIERRE BOURQUIN. ANDRE GRiissNER.

REFERENCES CITED The following references are of record in the file ofthis patent:

Jour. Amer. Chem. Soc, vol. 66 (Oct. 1944), page 1756 to 1757. (Copy inU. S. Patent Oflice Scientific Library, Washington, D. C.)

